Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay
Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modul...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/116742 https://orcid.org/0000-0002-7968-645X |
| _version_ | 1826204115750879232 |
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| author | Park, Daniel S. Liu, Brandon Winnicki, Sarah Reilly, Steven K. Andersen, Kristian G. Tewhey, Ryan Kotliar, Dylan A. Andersen, Kristian Mikkelsen, Tarjei Lander, Eric Steven Schaffner, Stephen F Sabeti, Pardis |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Park, Daniel S. Liu, Brandon Winnicki, Sarah Reilly, Steven K. Andersen, Kristian G. Tewhey, Ryan Kotliar, Dylan A. Andersen, Kristian Mikkelsen, Tarjei Lander, Eric Steven Schaffner, Stephen F Sabeti, Pardis |
| author_sort | Park, Daniel S. |
| collection | MIT |
| description | Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA’s capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology. |
| first_indexed | 2024-09-23T12:49:09Z |
| format | Article |
| id | mit-1721.1/116742 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:49:09Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1167422022-09-28T10:14:25Z Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay Park, Daniel S. Liu, Brandon Winnicki, Sarah Reilly, Steven K. Andersen, Kristian G. Tewhey, Ryan Kotliar, Dylan A. Andersen, Kristian Mikkelsen, Tarjei Lander, Eric Steven Schaffner, Stephen F Sabeti, Pardis Broad Institute of MIT and Harvard Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Department of Mathematics Tewhey, Ryan Kotliar, Dylan A. Andersen, Kristian Mikkelsen, Tarjei Lander, Eric Steven Schaffner, Stephen F Sabeti, Pardis Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA’s capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology. National Institutes of Health (U.S.) (grant DP2OD006514) National Institutes of Health (U.S.) (grant K99HG0081) National Institutes of Health (U.S.) (grant R01HG006785) 2018-07-03T12:29:03Z 2018-07-03T12:29:03Z 2018-02 2015-11 2018-06-28T15:48:22Z Article http://purl.org/eprint/type/JournalArticle 00928674 http://hdl.handle.net/1721.1/116742 Tewhey, Ryan, Dylan Kotliar, Daniel S. Park, Brandon Liu, Sarah Winnicki, Steven K. Reilly, Kristian G. Andersen, et al. “Direct Identification of Hundreds of Expression-Modulating Variants Using a Multiplexed Reporter Assay.” Cell 165, no. 6 (June 2016): 1519–1529. https://orcid.org/0000-0002-7968-645X http://dx.doi.org/10.1016/J.CELL.2016.04.027 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Park, Daniel S. Liu, Brandon Winnicki, Sarah Reilly, Steven K. Andersen, Kristian G. Tewhey, Ryan Kotliar, Dylan A. Andersen, Kristian Mikkelsen, Tarjei Lander, Eric Steven Schaffner, Stephen F Sabeti, Pardis Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title | Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title_full | Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title_fullStr | Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title_full_unstemmed | Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title_short | Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay |
| title_sort | direct identification of hundreds of expression modulating variants using a multiplexed reporter assay |
| url | http://hdl.handle.net/1721.1/116742 https://orcid.org/0000-0002-7968-645X |
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